In the last decade, the biological activity of several types and sub-types of the protein tyrosin kinase receptor family have been characterised such as, for example, the epidermal growth factor receptor EGFR and its subtypes ErbB-2 and ErbB-4 (Brignola et al., Journal of Biological Chemistry, Vol. 277, No. 2, pp. 1576-1585, 2002) or the vascular endothelial growth factor receptors VEGFR 1-3 together with its ligand VEGF and its four sub-types known to date (Jung et al., European Journal of Cancer, Vol. 38, pp. 1133-1140, 2002). Similar studies reported in previous reports show that the overexpression of some of these receptors is implicated in multiple forms of cancer. For example, studies have provided evidence that the epidermal growth factor EGF acts as a growth factor in tumours, and that the vascular endothelial growth factor VEGF is one of the most common mediators of tumor angiogenesis, which is essential for the growth and metastasis of solid tumours. Inhibitors of the receptors have thus been and are still evaluated for cancer therapy (see for example the article of Cerrington et al. In Advances in Cancer Research, Academic Press 2000, pp. 1-38).
Recent studies have also suggested to combine several receptor antagonists together, or in further combination with a chemotherapeutic agent or radiation. For example, WO 02/070008 suggests the combination of an antagonist specifically directed against the VEGF receptor with an antagonist specifically directed against the EGF receptor, optionally together with radiation or a chemotherapeutic agent, for the inhibition of tumour growth. As example of suitable specific antagonists, WO 02/070008 discloses monoclonal antibodies directed against the VEGF receptor and monoclonal antibodies directed against the EGF receptor.
Thus, a large number of protein tyrosine kinase receptor antagonists are currently in clinical development for the treatment of cancer (see for example the Expert Opinion Review of Laid & Cherrington in Expert Opin. Invest. Drugs, Vol. 12, No. 1, pp. 51-64, 2003). However, proof of efficacy for these substances, used alone or with other cancer therapies, in the treatment of oncological diseases, has so far not been achieved, either because of a lack of additional benefit over the standard therapy or because of the discovery of unacceptable side-effects.
For example, it has been recently published that an angiogenesis inhibitor which has already been clinically tested, also in conjunction with chemotherapy, namely the inhibitor with code name SU5416, developed by Pharmacia for the treatment of cancer, was associated with disturbing side effect, namely thromboembolic events (Ken Garber and Ann Arbor, Nature Biotechnology, Vol. 20, pp. 1067-1068, November 2002).
For the treatment of diseases of oncological nature, a large number of chemotherapeutic agents have already been suggested, which can be used as mono-therapy (treatment with one agent) or as combination therapy (simultaneous, separate or sequential treatment with more than one agent) and/or which may be combined with radiotherapy or radio-immunotherapy. In this respect, chemotherapeutic agent means a naturally occurring, semi-synthetic or synthetic chemical compound which, alone or via further activation, for example with radiations in the case of radio-immunotherapy, inhibits or kills growing cells, and which can be used or is approved for use in the treatment of diseases of oncological nature, which are commonly also denominated as cancers. In the literature, these agents are generally classified according to their mechanism of action. In this matter, reference can be made, for example, to the classification made in “Cancer Chemotherapeutic Agents”, American Chemical Society, 1995, W. O. Foye Ed.
Thus, within the meaning of the present invention, the following classes of chemotherapeutic agents are especially of interest, although not representing a limitation:                Synthetic small molecule VEGF receptor antagonists        Small molecule growth factor (GF) receptor antagonists        Inhibitors of the EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are not classified under the synthetic small-molecules        Inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins        Compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds        Compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents        Anti-metabolites        Naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics (BLM-group antibiotics)        Inhibitors of DNA transcribing enzymes, especially topoisomerase I or topoisomerase II inhibitors        Chromatin modifying agents        Mitosis inhibitors, anti-mitotic agents, or cell-cycle inhibitors        Proteasome inhibitors        Enzymes        Hormones, hormone antagonists or hormone inhibitors, or inhibitors of steroid biosynthesis        Steroids        Cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines or oral and parenteral tolerance induction strategies        Supportive agents        Chemical radiation sensitizers and protectors        Photochemically activated drugs        Synthetic poly- or oligonucleotides        Other chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agents, such as cytotoxic antibiotics, antibodies targeting surface molecules of cancer cells, inhibitors of metalloproteinases, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, or complexes of rare earth elements        
Further classes of compounds, so-far not classified as chemotherapeutic agents, which are naturally occurring, semi-synthetic or synthetic therapeutic agents, such as the non-steroidal anti-inflammatory drugs, especially the cyclooxygenase (COX) inhibitors and more specifically the COX-2 inhibitors, are also of interest for combination therapies.
Even if the concept of combining several therapeutic agents or therapies already has been suggested, and although various combination therapies are under investigation and in clinical trials, there is still a need for new and efficient therapeutic agents for the treatment of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, and there is still a need to develop further combinations which can show increased efficacy and reduced side-effects.
These diseases may as well be of oncological nature, which includes all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis or psoriasis.